Melanin-concentrating hormone (MCH) is a 19-amino acid cyclic, orexigenic neuropeptide, expressed predominantly in the lateral hypothalamus where it binds a cognate GPCR, MCHR1, and signals through complex neural networks to promote feeding and reduce energy expenditure.42-46 Infusion of MCH into rodents stimulates feeding and, on a chronic level, causes moderate weight gain.47-52 Increased expression of MCH in genetic models of obesity and the finding that MCH neurons express the leptin receptor suggest that leptin regulates MCH expression. Results of confirmatory in vitro and in vivo studies continue to emerge.53 56
Within the brain, high levels of MCHR1 mRNA have been found in areas that regulate food intake, olfaction, and motivated behavior, and expression levels increase upon fasting. In aggregate, these observations suggest a role for MCH, acting through MCHR1, in integration of taste, olfaction, and positive reward aspects of feeding behavior. MCH-transgenic mice are glucose intolerant, insulin resistant, and prone to weight gain on a standard chow diet.57 MCH-null mice are mildly hypophagic and lean and exhibit increased oxygen consumption and metabolic rate, reduced fat stores, and resistance to diet-induced obesity.58 Data for MCHRl-null mice59,60 are largely consistent with the phenotypic analysis of mice lacking the MCH ligand, although MCHR1-knockout mice are mildly hyperphagic on normal chow, suggesting they maintain lean body mass via increased basal metabolic rate.
In summary, phenotypic data for MCH and MCHR1-transgenic and -null mice indicate that both these gene products interact to modulate feeding behavior and energy balance. If the increase in resting energy expenditure in MCHR1-null mice can be replicated upon pharmacological blockade, this could be a key component in explaining mechanism of action and affording a therapeutic approach to obesity.
A second receptor, MCHR2, with similarly high affinity for MCH has been identified in the human brain.61-64 MCHR2 is distributed throughout the brain, especially in cortical areas; expression levels in the feeding centers of the hypothalamus are low relative to other brain regions. Due to differences in expression pattern from MCHR1, it has been suggested that MCHR2 may be involved in physiological effects of MCH other than feeding behavior and neuroendocrine modulation. Because rodent genomes do not encode MCHR2, it will be difficult to determine a role for this receptor subtype in the human brain.
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